rs33961459

chr11-5226687-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000518.5(HBB):c.205C>T(p.Leu69Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L69H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HBB NM_000518.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 0.203

Genes affected

HBB (HGNC:4827): (hemoglobin subunit beta) The alpha (HBA) and beta (HBB) loci determine the structure of the 2 types of polypeptide chains in adult hemoglobin, Hb A. The normal adult hemoglobin tetramer consists of two alpha chains and two beta chains. Mutant beta globin causes sickle cell anemia. Absence of beta chain causes beta-zero-thalassemia. Reduced amounts of detectable beta globin causes beta-plus-thalassemia. The order of the genes in the beta-globin cluster is 5'-epsilon -- gamma-G -- gamma-A -- delta -- beta--3'. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in NM_000518.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-5226686-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15271.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895
• PP5: Variant 11-5226687-G-A is Pathogenic according to our data. Variant chr11-5226687-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 15613.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HBB	NM_000518.5	c.205C>T	p.Leu69Phe	missense_variant	2/3	ENST00000335295.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HBB	ENST00000335295.4	c.205C>T	p.Leu69Phe	missense_variant	2/3	1	NM_000518.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

alpha Thalassemia;C0002895:Hb SS disease;C0019025:Hereditary persistence of fetal hemoglobin;C0700299:Heinz body anemia;C1840779:Methemoglobinemia, beta-globin type;C1858990:Dominant beta-thalassemia;C1970028:Malaria, susceptibility to;C4693822:Erythrocytosis, familial, 6;CN322236:Beta-thalassemia HBB/LCRB Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 06, 2021

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Oct 31, 2022

The Hb Loves Park variant (HBB: c.205C>T; p.Leu69Phe, also known as Leu68Phe when numbered from the mature protein, rs33961459, HbVar ID: 375) is reported in the literature in the heterozygous state in multiple individuals affected with microcytic anemia and in one individual with mild cyanosis (Ferreira 2006, HbVar database and references therein). In one instance, this variant was observed in an affected proband but was not found in either parent despite demonstrated parentage, indicating a de novo origin (Ferreira 2006). This variant has been reported as stable with decreased oxygen affinity. This variant is reported in ClinVar (Variation ID: 15613) and is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 69 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.742). Additionally, another amino acid substitution at this codon (p.Leu69Pro, also known as Hb Mizuho, HbVar ID: 373) has been reported de novo in multiple individuals with hemolytic anemia and is considered disease-causing (HbVar database and references therein). Based on available information, the Hb Loves Park variant is considered to be pathogenic. References: Link to HbVar: https://globin.bx.psu.edu/hbvar/hbvar.html Ferreira C et al. Hemoglobin Loves Park (beta68 (E12) Leu-->Phe): report of five cases including one originating from a de novo mutation. Am J Hematol. 2006 Apr;81(4):256-61. PMID: 16550507. -

HEMOGLOBIN ROCKFORD Other:1

other, no assertion criteria provided

literature only

OMIM

Dec 12, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
Cadd	Benign	18
Dann	Uncertain	1.0
DEOGEN2	Benign	0.040	T;T;.;T
Eigen	Benign	0.011
Eigen_PC	Benign	-0.14
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.7	M;M;.;.
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.0	D;.;.;D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.014	D;.;.;D
Sift4G	Uncertain	0.059	T;.;.;.
Polyphen		0.65	P;P;.;.
Vest4		0.88
MutPred		0.69		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.71
MPC		0.14
ClinPred		0.96	D
GERP RS		-0.46
Varity_R		0.54
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs33961459; hg19: chr11-5247917;